Globally, over 400 million people are chronically infected with hepatitis B virus (HBV), and more than 12 million reside in the United States alone. Of those chronically infected patients, up to 40 percent will eventually develop complications of liver failure from cirrhosis or development of hepatocellular carcinoma (HCC). One of the key diagnostic symptoms of chronic HBV (CHB) is the high serum levels of the hepatitis B surface antigen (HBsAg or sAg) which may play a role in suppression of the host innate immune response. Clinical data in the recent years suggest that sustained virologic response is often associated with on-treatment HBsAg decline during the early phase of the treatment (as early as week 8). CHB patients who experienced larger and faster decreases in serum HBsAg levels achieved significantly higher rate (˜40%) of sustained virologic response as defined by sustained viral control post treatment. Current treatment options, comprising mainly of nucleoside/nucleotide inhibitors of the viral DNA polymerase, focus on reduction in the level of viremia and toleration of hepatic dysfunction, may have adverse side-effects, and select for drug-resistant virus variants during long term therapy. More importantly, these therapies cannot eradicate the intrahepatic HBV cccDNA (covalently closed circular DNA) pool in chronic hepatitis B patients or limit the transcription of HBsAg from the pre-existing cccDNA, nor do they affect the secretion of synthesized HBsAg into patients' blood to counteract the host innate immune response. As a result, these HBV treatments are in most cases life-long therapy and discontinuation often leads to virological relapse. Based on these observations but without wishing to be bound by any particular theory, this disclosure contemplates that novel therapeutic approaches, in conjunction with current nucleoside/nucleotide inhibitors, that target 1) elimination of the cccDNA pool, or 2) reduction of cccDNA-dependent transcription and synthesis/secretion of HBsAg will significantly enhance sustained virologic response among CHB patients and achieve a meaningful clinical cure of this debilitating viral disease.
There exists the need for novel treatments for HBV.